ABSTRACT Systemic Autoimmune Diseases (SAD) are clinically complex and molecularly heterogeneous. Among them, Sstemic Lupus Erythematosus (SLE) is characterized by widespread inflammation and development of autoantibodies against nucleic acids such as double stranded DNA (dsDNA) and RNA-binding protein complexes. While genetic analyses of monogenic SLE cases provide insight into disease pathogenesis, the interaction between complex genetic backgrounds and the environment underlie the more common, non- Mendelian forms of SLE. SLE blood immunomonitoring has provided significant insights into disease pathogenesis, and Dr. Pascual's (PD) group has described fundamental alterations in innate cytokine- (Type I interferon IFN), myeloid cell- (monocytes, neutrophils and dendritic cells -DCs-) as well as plasmablast-related pathways in SLE and identified transcriptional signatures related to these cells and pathways that correlate with disease activity in patients. In addition to cells, the blood carries protein, lipid and nucleic acid cargo of cellular origin within extracellular vesicles (EVs), which include microparticles (MPs) and exosomes. We have demonstrated that such EVs reflect the state of their parental cells and tissues, have crucial roles in long distance intercellular communication, and could serve as biomarkers of disease progression and heterogeneity. Importantly, major histocompatibility complex class II (MHC II) proteins are found on exosomes derived from antigen-presenting cells such as B-cells or DCs. Moreover, proteins, genetic material (e.g., mRNAs, miRNAs, lnRNAs, DNA), metabolites and lipids, are selectively packaged into exosomes, which can in turn horizontally transfer their cargo to recipient cells, thereby acting as vehicles of intercellular communication in both physiological and pathological conditions. Here, we will test the hypothesis that exosomes mediate complex systemic interactions that underlie SLE and other SADs that are being studied under the ACE collaborative program. Since little is known regarding the role of exosomes in autoimmunity in general and SLE in particular, we propose to: 1) characterize the size, number, protein, DNA and RNA cargo of plasma- derived exosomes from patients; 2) investigate the immunomodulatory functions of exosomes in the context of SLE- and other SADs and 3) determine the biomarker potential of exosomes in deconvoluting disease heterogeneity and advancing patient classification. We expect that these studies will contribute to further decode pathogenic molecular pathways and biomarkers associated with systemic autoimmunity towards personalized therapeutic interventions.